Several noninvasive methods of imaging body organs have been developed over the past decade. These procedures are based on the tendency of a body organ to concentrate some detectable chemical. Particularly useful chemicals are those which emit gamma radiation. Subsequent scanning of the organ with a gamma ray camera provides an image of the organ from which diagnostic information can be obtained. .sup.99m Tc(Tc-99m) has found particular utility in this area because of its half-life and gamma ray emission.
The metastable isotope Tc-99m has a six hour half-life and an emission spectrum of 99% gamma radiation at 140 KeV and has a specific activity 5.28.times.10.sup.9 millicuries per gram. Tc-99m has also become readily available in hospitals through the use of selective elution from a molybdenum-99 generator. The isotope Mo-99 produces Tc-99m as a radioactive decay product.
Although detecting radiation from a radiation emitting pharmaceutical has proven particularly useful in noninvasive organ imaging, particular radiopharmaceuticals are still needed. There is a particularly strong need for an effective myocardial imaging agent. There are two types of myocardial imaging agents, the positive agents which accumulate in an infarcted area and negative agents which accumulate in a normal heart but not in the infarcted area. Using a positive agent causes an infarcted area to show up as a hot spot of radioactivity whereas with a negative agent the infarcted area shows up as a cold area against a hot background.
Over the past couple of years several different Tc-99m compounds have been disclosed for use as positive myocardial imaging agents. These different imaging agents, having substantially different chemistry, have found various levels of utility in different mammals. To date it is still a goal of nuclear medicine to find a more effective negative myocardial imaging agent particularly suited for the human heart.
The first work with myocardial imaging agents formed from Tc-99m was conducted by Deutsch et al as disclosed in U.S. Pat. No. 4,489,054. Deutsch et al determined that cationic lipophilic complexes of Tc-99m provided a useful myocardial image in mammals. This work provided particularly good images with certain mammals particularly dogs. Technetium can assume several valence states ranging from +7 to -1. The methods disclosed in the Deutsch et al U.S. Pat. No. 4,489,054 disclosed technetium complexes in the +3 state. These subsequently were found to provide a relatively poor image of the human heart.
Further work conducted by Deutsch, Libson et al indicated that the complexes of Tc(I)-99m provided more useful heart images. These provided particularly good images of cat hearts. Unfortunately with humans these images were obscured by the accumulation of the technetium complex in the liver. This interfered with obtaining a very good image of the heart. This is disclosed in Deutsch et al U.S. application Ser. No. 628,482 filed July 6, 1984 incorporated herein by reference. Additional work disclosed in Deutsch et al application Ser. No. 628,482 filed July 6, 1984 indicated that .sup.99m Tc(I) compounds when ligated to phosphonate and phosphonite ligands cleared the liver more quickly and provided an even better myocardial image. These clear the liver exceptionally well but do not clear from the blood to permit a useful image of the heart. Other cationic ligated complexes of .sup.99m Tc are disclosed for example in Rodriguez U.S. Pat. No. 4,497,790; Glavan et al U.S. Pat. No. 4,374,821; and Tweedle U.S. Pat. No. 4,455,291. Other technetium compounds are disclosed in European patent application 0123240.